eosinophilic digestive diseases: eosinophilic esophagitis ... · pdf filethe pathophysiology...

834 J Formos Med Assoc | 2009 • Vol 108 • No 11

REVIEW ARTICLE

Eosinophilic digestive diseases (EDD), including

eosinophilic esophagitis, eosinophilic gastroen-

teritis, and eosinophilic colitis, are relatively rare

gastrointestinal disorders. However, these condi-

tions are becoming increasingly recognized and an

area of increasing interest of research. Although

clinical presentation of the disorders varies widely,

the pathophysiology underlying all three is sus-

pected to be hypersensitivity related. Unfortu-

nately, there are no large, randomized, controlled

trials to guide treatment in EDD, and current man-

agement is extrapolated from therapies for other

atopic conditions. The mainstay of therapy is

corticosteroids and avoidance of food antigens.

Pathophysiology of EDD

Under normal, non-pathologic conditions, the gas-

trointestinal tract is the only non-hematopoietic

organ to contain eosinophils,1 with the cecal and

appendiceal region having the highest concen-

trations.2 Under normal conditions, the majority

of gastrointestinal eosinophils reside in the

lamina propria.3 The role of eosinophilia in par-

asitic infections of the gastrointestinal tract has

long been recognized. However, emerging evi-

dence suggests that eosinophils may play a role

in several other conditions, including EDD. The

pathogenesis of eosinophilic gastrointestinal dis-

eases is not clearly understood. But, given the

high correlation with other atopic conditions, a

hypersensitivity response is strongly suspected.

It is postulated that exposure of the gastrointesti-

nal mucosa to antigens promotes a Th-2 mediated

immune response. Th-2 cells produce interleukin

(IL)-4, IL-5 and IL-13, and promote the produc-

tion of eosinophils as well as IgE.4–6 Allergic

conditions, including asthma and allergic rhini-

tis, are also found to have a Th-2 mediated

©2009 Elsevier & Formosan Medical Association. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1Division of Gastroenterology-Hepatology, Department of Medicine, and 2Department of Pathology, University ofConnecticut Health Center, Farmington, Connecticut, USA.

Received: August 28, 2009Revised: September 24, 2009Accepted: October 2, 2009

*Correspondence to: Professor George Y. Wu, Division of Gastroenterology-Hepatology, Department of Medicine, University of Connecticut Health Center,Farmington, CT 06030, USA.E-mail: [email protected]

Eosinophilic Digestive Diseases: EosinophilicEsophagitis, Gastroenteritis, and ColitisAllison Shifflet,1 Faripour Forouhar,2 George Y. Wu1*

Eosinophilic digestive diseases (EDD) are relatively rare disorders associated with increased gastrointesti-nal eosinophilic infiltrates without any underlying primary etiology. The pathophysiology of EDD is un-clear, but is suspected to be related to a hypersensitivity reaction given its correlation with other atopicdisorders and clinical response to corticosteroid therapy. Given the overall relative increase of variousatopic conditions, it is important for clinicians to understand the presentation and diagnosis and treat-ment options available. We present here a review of EDD, including the proposed pathophysiology, diag-nosis and current treatment options for these disorders. [J Formos Med Assoc 2009;108(11):834–843]

Key Words: atopy, colitis, eosinophils, esophagitis, gastritis

response, which suggests that EDD should

be included within the spectrum of atopic

diseases.

Eosinophilic Esophagitis

Eosinophilic esophagitis is the most commonly

recognized EDD. Patients often present with

symptoms similar to gastroesophageal reflux dis-

ease; however, they are not responsive to tradi-

tional antireflux therapy. In fact, there is

emerging data to suggest that use of acid-sup-

pressive medications may predispose patients to

the development of eosinophilic esophagitis.7

The alteration of gastric pH caused by antisecre-

tory medications has been shown to affect pro-

tein digestion, allowing a larger percentage of

ingested protein to be absorbed in larger frag-

ments, potentially inducing an immunologic re-

sponse.8 Additionally, recent studies by Mullin

et al demonstrated increased permeability in the

mucosa of the upper gastrointestinal tract in pa-

tients taking acid-suppressive medications.9,10

This increased permeability may allow poten-

tially allergenic digestion products to permeate

gastric mucosa and induce an immunologic

reaction.

EpidemiologyEosinophilic esophagitis is more common in

Caucasians and males.11–13 The reported incidence

is approximately six per 100,000.14 However, in-

creased awareness of the disease over the past

several years has led to an increasing number of

cases identified. A higher incidence of eosino-

philic esophagitis is noted in patients with other

atopic conditions.11–14

Clinical presentationThe main presenting complaints of eosinophilic

esophagitis are similar to those of gastroesoph-

ageal reflux disease, including epigastric burning

and pain, regurgitation, nausea and vomiting.

However, symptoms are not responsive to stan-

dard antireflux therapy. Additionally, patients

may present with symptoms of dysphagia and

possible food impaction symptoms.15

DiagnosisThe diagnosis of eosinophilic esophagitis relies

on endoscopic biopsy. Visualization of the esoph-

agus during endoscopy may appear abnormal,

including esophageal furrows (Figure 1) and stric-

tures, white plaques, or mucosal rings.14,16 How-

ever, in one third of patients, the appearance of

the esophagus may be normal.17 There are no

pathognomonic radiologic findings in eosino-

philic esophagitis. However, the most common

finding on barium studies is esophageal strictures.

In one retrospective analysis, 71% of patients

had esophageal strictures on barium studies;

50% of these strictures were noted to be of a dis-

tinctive ring-like character, which is increasingly

being recognized in association with eosinophilic

esophagitis.18

PathologyEosinophilic esophagitis may be associated with

eosinophilic gastroenteritis or may be found in

isolation. Because it is not unusual to find eosin-

ophils in mucosal biopsies of reflux esophagitis,

the number of eosinophils should exceed 25/

high-powered field and preferably involve submu-

cosa for positive histologic diagnosis (Figures 2A

and 2B). Patchiness of the disease may create

Eosinophilic digestive diseases

J Formos Med Assoc | 2009 • Vol 108 • No 11 835

Figure 1. Endoscopic image from an adult male who pre-sented with dysphagia. Esophageal biopsy demonstratedeosinophilic infiltrates.

A. Shifflet, et al


Figure 2. Cross sections of normal esophagus (A) contrasted with eosinophilic esophagitis (B). Normal gastric mucosa (C) versus gastricmucosa with eosinophilic infiltrates (D). Normal colon (E) compared with eosinophilic colitis (F). [Images A–F are at 400× magnification.]Eosinophilic cryptitis (G) at 400× magnification compared with eosinophilic cryptitis and marked infiltration of lamina propria (H) at 1000×magnification. Arrows indicate eosinophils in the abnormal specimens (B, D, F).

A

C

E

G H

F

D

B

false-positive results unless generous multiple

samples are obtained.

Eosinophilic Gastroenteritis

Eosinophilic gastroenteritis is a rare condition

involving eosinophilic infiltrates of gastrointesti-

nal tissue causing a wide array of gastrointestinal

symptoms. The diagnosis of eosinophilic gastro-

enteritis requires a high degree of clinical suspi-

cion, given the relatively nonspecific history and

physical examination findings. Eosinophilic gas-

troenteritis should be considered in the differen-

tial diagnoses of any patient who presents with

abdominal pain or other nonspecific gastroin-

testinal complaints without any clear etiology

on diagnostic evaluation. A definitive diagnosis

can be made by endoscopic biopsy displaying in-

creased eosinophilic infiltrates and exclusion of

any primary etiology causing hypereosinophilia.

EpidemiologyEosinophilic gastroenteritis is a rare disease, with

a peak incidence between the ages of 20 and 50

years.19 While the actual incidence is unknown,

there have been several case reports in the litera-

ture, particularly in the past 30–40 years, with the

initial case report published in 1937.20 Given

the wide variety of presentations in addition to

the relatively nonspecific symptoms of this dis-

ease, the incidence has likely been underreported.

There is an increased incidence of eosinophilic

gastrointestinal disease in patients with other

atopic conditions, such as asthma, allergic rhini-

tis, atopic dermatitis, and food and environmental

allergies. This may relate to the similar underly-

ing reactive processes of these disorders, includ-

ing increased eosinophils, mast cells, IL-4, IL-5,

IL-13 and chemokines.21

Clinical featuresThe clinical features seen in eosinophilic gastro-

enteritis vary based on the region and depth of

the gastrointestinal tract affected by eosinophilic

infiltration.

Mucosal eosinophilic gastroenteritis

Symptoms of mucosal eosinophilic gastroenteritis

include nonspecific complaints such as abdomi-

nal pain, nausea, vomiting and diarrhea as well as

anemia due to fecal occult blood loss and protein

wasting enteropathy.22 Given these nonspecific

symptoms, the diagnosis of mucosal eosinophilic

gastroenteritis requires high clinical suspicion.

The prevalence of mucosal eosinophilic gastroen-

teritis varies widely between studies (25–100%).

However, the higher incidence of this subtype

may be due to the more relative ease of diagnosis

via endoscopic biopsy.23,24

Muscularis eosinophilic gastroenteritis

Muscular eosinophilic gastroenteritis often pres-

ents with signs and symptoms of gastric outlet

and intestinal obstruction, and typically colicky

abdominal pain.25,26 Muscular eosinophilic gas-

troenteritis is the second most common subtype,

found in 13–70% of cases.23

Subserosal eosinophilic gastroenteritis

Subserosal eosinophilic gastroenteritis is the least

common subtype, accounting for only 12–40%

of cases.23 Subserosal eosinophilic gastroenteritis

frequently presents with ascites and bloating,27

and often has a higher level of peripheral eosino-

philia.28 This subset of patients typically has bet-

ter clinical response to steroid treatment, but often

with a more significant number of relapses.28

DiagnosisThe diagnosis of eosinophilic gastroenteritis re-

quires a high index of suspicion, given its wide

array of nonspecific symptoms and relatively low

incidence. A clinical history of other atopic condi-

tions such as asthma, atopic dermatitis, and food

and environmental allergies should heighten sus-

picion for eosinophilic gastroenteritis. Patients

with eosinophilic gastroenteritis may appear chro-

nically ill on physical examination, with signs of

malnutrition due to malabsorption. Suggestive

findings on laboratory data are peripheral eosin-

ophilia. But this finding is extremely variable.19

Radiographic changes in patients with eosinophilic



gastroenteritis are also variable and are absent in

up to 40% of cases.29 Upper gastrointestinal se-

ries may show an irregular and lacy antral surface

of the stomach or thickening of the circular folds

and wall of the small bowel.30 Additionally, stric-

tures secondary to eosinophilic gastroenteritis may

be evident on imaging. The endoscopic appear-

ance of eosinophilic gastroenteritis is relatively

nonspecific and most notable in the mucosal

subtype. Abnormalities include erythema, ulcer-

ations or focal erosions, and thickening of folds

and friability.31

PathologyDefinitive diagnosis is made by histological

evidence of eosinophilic infiltration on biopsy.

The majority of studies have used a definition

of > 20 eosinophils/high-powered field in the

lamina propria for eosinophilic gastroenteritis

(Figures 2C and 2D).19 Involvement of gastric

mucosa is often patchy and multiple biopsies

should be obtained from various regions to im-

prove yield. It involves all layers of the wall and

is typically associated with edema (especially in

the submucosa and muscle), increased vascular-

ity, and fibrosis. Other inflammatory cells are also

increased. In particular, increased number and

degranulation of mast cells have come to atten-

tion more recently. Occasionally, necrotizing gran-

ulomata are noted. Involvement of subserosa

may be associated with eosinophilic ascites and

peritonitis.

Since endoscopic biopsies are typically lim-

ited to mucosa, pathologic findings in this region

carry special significance for everyday diagnosis.

Significant patchy or diffuse eosinophilic infil-

tration of lamina propria is a frequent finding.

However, the number of eosinophils varies con-

siderably in normal mucosa. Thus, other findings

such as epithelial infiltration, eosinophilic cryp-

titis and degranulation, and involvement of mus-

cularis mucosa and submucosa are important to

increase the reliability of histologic diagnosis. In

addition, the frequently patchy nature of the dis-

ease creates high false-negative rate unless gener-

ous and multiple biopsies are obtained.

Once a diagnosis of eosinophilic gastroen-

teritis is made, some clinicians elect to perform

allergy evaluation to determine the inciting anti-

gen. Methods of allergy testing include skin prick

or patch tests and radioallergosorbent tests to

detect IgE antibody formation against various

ingested antigens. This can assist in development

of an elimination diet to avoid antigen exposure.

Eosinophilic Colitis

Eosinophilic colitis is the least common EDD

and varies in clinical presentation depending on

the region and layer of colon affected. Diagnosis

of eosinophilic colitis also relies on biopsy with

pathologic evaluation.

EpidemiologyEosinophilic colitis is the rarest EDD. It mainly

affects neonates and young adults. Eosinophilic

colitis appears to affect both sexes equally.32

Clinical presentationThe clinical symptoms of eosinophilic colitis may

vary depending on the intestinal layer affected,

similar to eosinophilic gastroenteritis. Eosino-

philic colitis affecting the mucosa often presents

with malabsorption, diarrhea, and protein wast-

ing, whereas disease affecting the muscularis

often manifests as intestinal obstruction and

colonic thickening. Eosinophilic colitis affecting

the serosa mainly presents as ascites with fluid

analysis showing the majority of cells to be

eosinophils.33–35

DiagnosisThe mainstay of diagnosis for eosinophilic coli-

tis is biopsy. A small number of eosinophils may

be seen in various regions of the colon under nor-

mal conditions, and at present there is no gen-

eral consensus for differentiating normal versus

abnormal levels of eosinophilia in the colon. Ra-

diologic findings of eosinophilic colitis also de-

pend on the region and layer affected, but may

show strictures or thickening of the bowel wall.33

A. Shifflet, et al


PathologyEosinophilic colitis is more problematic to diag-

nose because of marked variability in the num-

ber of eosinophils in the normal population and

in various geographic sites. The concentration

of eosinophils is variable depending on the re-

gion of the colon. Eosinophils are more concen-

trated in the cecum and ascending as compared

to the left colon. Eosinophils comprise up to 3%

of the inflammatory cells in normal colonic mu-

cosa (Figure 2E), and this percentage may in-

crease significantly without any correlating clinical

complaint or disease. Thus, the presence of ede-

ma in the muscularis and submucosa, presence

of eosinophils (Figure 2F) in the epithelium of the

crypts (Figure 2G), degranulation, and involvement

of muscularis mucosa and submucosa (Figure 2H)

are particularly important in formulating a diag-

nosis of eosinophilic colitis. Generous and mul-

tiple biopsy samples are necessary for diagnosis.

Often, eosinophilic cryptitis is observed in asso-

ciation with chronic inflammatory bowel disease,

particularly Crohn’s disease, and this is impor-

tant in the differential diagnosis for eosinophilic

colitis. On rare occasions, eosinophilic colitis or

gastroenteritis manifest themselves as localized

tumor masses and may present with a clinical

picture of obstruction. In such cases, eosinophilic

venulitis may dominate the pathology.

Differential Diagnosis

Eosinophilic infiltration of the gastrointestinal

mucosa can be seen secondary to a variety of

other conditions. It is important to evaluate pa-

tients for secondary causes prior to diagnosis of

primary EDD. The classic association is in the

setting of parasitic infections, such as Ascaris,

Anisakis, Trichuris, schistosomiasis, Ancylostoma

caninum (hook worm), and Enterobius vermicularis

(pinworm).36–41 Case reports of Toxocara canis

and Strongyloides causing eosinophilic ascites have

been reported as well.42,43 Evaluation of stool for

ova and parasites or larvae identified on biopsy

confirms primary parasitic infection as the etiology

for eosinophilic infiltration in these cases. Addi-

tionally, several medications have been implicated

in eosinophilic infiltration of gastric mucosa.

The more commonly utilized medications that

have been implicated include azathioprine, gem-

fibrozil, enalapril, and carbamazepine.44–47 Other

causes of secondary gastrointestinal eosinophilia

include connective tissue diseases and vasculi-

tis.48,49 Occasionally, inflammatory bowel disease

may be associated with gastrointestinal eosino-

philic infiltrates as well as peripheral eosinophilia,

as a component of the inflammatory response in

inflammatory bowel disease.50 Hypereosinophilia

syndrome may also be a secondary cause of

eosinophilic gastroenteritis. Hypereosinophilia

syndrome is a rare condition with significant

peripheral eosinophilia for an extended period

of time (> 6 months) and associated infiltration

and end-organ damage related to hypereosino-

philia.51 Clinically, patients with eosinophilic

esophagitis present with complaints similar to

gastroesophageal reflux disease. A recent study by

Sayej et al revealed that high-dose proton pump

inhibitor therapy may be useful in differentiating

patients with eosinophilic esophagitis from those

with non-eosinophilic esophagitis.52 An addi-

tional study by Dellon et al identified a variety of

clinical, endoscopic and histologic findings that

may aid in distinguishing eosinophilic esophagi-

tis from gastroesophageal reflux disease. They

retrospectively reviewed 377 patients with either

gastroesophageal reflux disease or eosinophilic

esophagitis and found that younger age, symp-

toms of dysphagia, history of food allergies,

endoscopic evidence of esophageal rings, linear

furrows, white plaques or exudates, and absence

of hiatal hernia, as well as pathologic evidence of

higher maximum eosinophil count and presence

of eosinophil degranulation independently pre-

dicted eosinophilic esophagitis.53

Treatment of EDD

At present, there are no large, randomized, con-

trolled trials to guide treatment in eosinophilic



gastroenteritis. The majority of data is from

smaller case series or extrapolated from the man-

agement of other atopic conditions. Cortico-

steroid therapy plays a large role in the treatment

of this condition. Given the suspected inflamma-

tory and hypersensitivity pathology of EDD,

steroids are a reasonable treatment option. Sev-

eral small, uncontrolled studies have evaluated

the efficacy of steroids in the various types of

EDD and shown significant improvement in

symptom management. However, no histologic

correlation has been shown.27,54,55 The optimal

duration of corticosteroid therapy has not yet

been established. Often, a dosing strategy similar

to that used in inflammatory bowel disease has

been utilized (1–2 mg/kg/day for 8 weeks fol-

lowed by a gradual taper).23 Topical corticoste-

roid treatment has also been utilized in patients

with eosinophilic esophagitis. A small study of

21 adult patients evaluated the effects of a 12-

month course of oral fluticasone propionate.56

All patients in this trial had complete resolution

of their dysphagia symptoms per assessment at

4 months post-completion of therapy. However,

a second study that evaluated patients who had

received oral fluticasone treatment approximately

3 years after completion of therapy found that

91% of patients had experienced recurrence of

their dysphagia symptoms.57

Alternative immune-modifying medications,

including mast cell inhibitors (sodium cromo-

glycate, 200 mg four times daily)58 and leukotriene

receptor antagonists have also been evaluated in

this condition. These studies are largely observa-

tional and the medications were often evaluated in

combination with other treatment modalities.59–61

In one case report by Urek et al, montelukast

10 mg/day provided symptom improvement in

an adolescent male with eosinophilic gastroen-

teritis.62 Additional case reports also demonstrated

symptom improvement.63,64 However there are

no large randomized trials evaluating efficacy or

correlating histologic improvement. Leukotriene

receptor antagonists have been shown in multi-

ple case reports to improve symptoms and pro-

vide an alternative to corticosteroids for chronic

maintenance therapy. The majority of case reports

involved children with eosinophilic gastroenteri-

tis or eosinophilic esophagitis and used dosages

of montelukast ranging from 10 mg daily to

40 mg daily.64–66 Additionally, Friesen et al re-

ported a double-blinded, randomized, controlled

study evaluating the efficacy of montelukast

(10 mg daily) in 40 children and adolescents

with eosinophilic duodenitis. Their results showed

significant symptom improvement in the mon-

telukast arm (62%) versus the placebo arm

(32%).67

As mentioned above, it is postulated that EDD

are triggered by food antigen exposure. Allergy

testing can aid in the identification of specific

antigens and development of an elimination diet.

The majority of data evaluating diet modifica-

tion have been obtained from the pediatric pop-

ulation. In a large study, specific elimination diets

based on food sensitivities resulted in improve-

ment in symptoms and esophageal biopsy in 75%

of patients.68 However, allergy testing has low

sensitivity and specificity with high false-positive

rates and should be cautiously interpreted. Other

studies have evaluated the effect of a trial of em-

piric elimination diet, with removal of the six most

common food allergens (milk, soy, egg, wheat,

nuts and seafood). In a small study of 35 patients

who were placed on an empiric elimination diet

for a 6-week trial, 74% showed improvement on

esophageal biopsy.69

Given the relative lack of data at this time,

there is no definitive treatment regimen for pa-

tients with EDD. However, it is reasonable to

consider a course of corticosteroid treatment

(1–2 mg/kg/day for 8 weeks followed by a gradual

taper) for the management of acute symptoms in

the appropriate clinical setting. Topical steroids,

including oral fluticasone (fluticasone inhaler

220 mmol/puff, two puffs twice daily), may also

be considered as a treatment option. Some pa-

tients may require chronic maintenance therapy

and steroid-sparing options, including mast cell

inhibitors (sodium cromoglycate, 200 mg four

times daily) and leukotriene receptor antago-

nists (montelukast 10–40 mg daily). Empiric diet

A. Shifflet, et al


modification or allergy testing with specific diet

modifications may be an alternative option in

motivated patients.

Conclusion

EDD, including eosinophilic esophagitis, eo-

sinophilic gastroenteritis and eosinophilic coli-

tis, are rare conditions involving gastrointestinal

eosinophilic infiltrates and associated gastroin-

testinal symptoms without a primary etiology

for hypereosinophilic infiltrates. The pathophys-

iology of this condition is not well understood,

but a hypersensitivity mechanism is suspected

given its increased association with other atopic

conditions and clinical improvement with corti-

costeroids. The definitive diagnosis of EDD is

made with endoscopic biopsy displaying increased

eosinophilic infiltrates and the absence of any

primary disorders that may cause secondary

eosinophilic infiltrates. At this time, there is min-

imal data to guide EDD treatment. Treatment reg-

imens are extrapolated from therapies for other

atopic disorders and current evidence for efficacy

is limited to case reports and smaller studies.

Based on this data, it is reasonable to use corti-

costeroids in the acute setting and, if necessary,

mast cell inhibitors, leukotriene receptor antago-

nists and diet modification for chronic mainte-

nance. Additional studies are needed to further

delineate the pathophysiology of EDD, and

larger randomized, controlled studies are needed

to determine optimal treatment regimens.

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